Many human neurodegenerative diseases are poorly understood as well as untreatable, including Parkinson's, Alzheimer's and Huntington's diseases. For some familial forms of these diseases, mutations in specific gene products associated with disease are known, allowing the possibility to model the disease in simple systems in order to address mechanisms of degeneration of degeneration and to pioneer novel treatments. Toward this end, we applied a new approach to the problem of polyglutamine- induced neurodegeneration by developing a model for this class of human disease in the fruit fly Drosophila melanogaster. These experiments demonstrated that the fundamental molecular mechanisms of polyglutamine-induced neurodegeneration are conserved in Drosophila, such that Drosophila genetics can now be applied to investigate these human diseases in order to address mechanisms of degeneration and define new means of treatment. We now propose to apply this same strategy to address mechanisms and treatments of human neurodegenerative diseases associated with alpha-synuclein (alpha-syn) pathology. Mutations in the alpha-syn gene are pathogenic for hereditary Parkinson's disease, and the wild-type alpha-syn is the major protein component of pathological aggregates called Lewy Bodies that are present not only in sporadic Parkinson's disease, but also in Alzheimer's disease and select other human neurodegenerative diseases. An alpha-syn fragment is also implicated as component of senile plaques in Alzheimer disease. Purified recombinant alpha-syn aggregates in vitro into filaments that resemble Lewy Bodies, suggesting that alpha-syn may be critical to Lewy Body formation and potentially causal in neurodegeneration. Our preliminary data suggest that expression of alpha-syn in Drosophila will provide a system in which to study and define ways to prevent synuclein- induced degeneration. Here we propose to generate addition transgenic flies expressing alpha-syn, its mutant forms and homologues, and characterize their ability to induce neurodegeneration and protein aggregation. We will develop methods to prevent alpha-syn pathology by identifying suppressor genes. By applying the power of Drosophila genetics to address conserved features of synuclein pathology, these studies pioneer new approaches to cures and treatments for human neurodegenerative diseases.